Targeting and killing the non-malignant cells that surround and support a cancer can stop tumor growth in mice, reports a research team based at the University of Chicago Medical Center in the March 1, 2008, issue of the journal Cancer Research. The discovery offers a new approach to treating cancers that are resistant to standard therapy.
Many solid tumors develop elaborate mechanisms to prevent recognition and elimination by the immune system. Due to their genetic instability they often discard the tumor antigen-presenting cell-surface structures that alert the immune system that these cells are harmful. Without these “flags,” the white blood cells fail to recognize and kill infected or cancerous cells. These tumors then often grow rapidly and resist treatment with chemotherapy or efforts to boost the immune system's response to the tumor.
But the stroma, the layers of cells that surround a tumor, can accumulate tumor antigens and present them on their surface. These genetically stable surrounding cells retain the molecules that present tumor antigens, which makes them a good target for immunotherapy, and they often play an enabling role in tumor growth.
“We already knew that targeting the stroma is essential for eradicating established large tumors, because the stroma is like the 'root of the tumor," said study author Hans Schreiber, MD, PhD, professor of pathology at the University of Chicago. “However, effects of current treatments that target stroma are usually transient and not cancer-specific."
"Since cancer is a genetic disease," he said, "we wondered whether mutant proteins are released into the surroundings and picked up by the stroma. If so, we can target the root of the cancer in a cancer-specific way to arrest or eradicate a tumor."
They injected T cells, the immune system's warriors, into mice with large established cancers. These T cells, specifically engineered to recognize the tumor antigen, had no direct impact on the cancerous cells but managed to kill stromal cells. This reduced tumor size and stopped the growth of tumors for more than 80 days.
Although targeting the stroma didn't eliminate all cancer cells, it did stop or slow the growth of well-established cancers after a single injection of T cells.
“Such growth arrest in patients would be an admirable achievement for many cancers,” the authors write, "and could also be used as an adjuvant to other therapies."
Tumor eradication is obviously preferable to tumor arrest, the authors note. "We can't target cancer cells when they have lost their antigen-presenting molecules,” said co-author Bin Zhang, PhD, a former postdoctoral fellow in Schreiber's laboratory and now assistant professor at the University of Texas Health Sciences Center, San Antonio. “So stroma becomes an ideal alternative target for T cells."
One concern was that other, healthy cells in tissues like the spleen could also pick up the antigens and become a target for T cells, said Zhang. “We did not see this," he added. "Only tumor-derived stromal cells appear to pick up and present tumor antigen.”
The next step is to test this approach for melanoma, breast and colon cancer, Zhang said. “We know that stromal cells often present tumor-antigen in these tumors, but have not yet performed T cell therapy on these mice.”
They are also studying this approach for human cancers. Early results suggest that "this approach might be useful for the human situation as well,” Zhang said.
The National Institutes of Health and the University of Chicago Cancer Research Center supported this research. Additional authors of the paper include Andrea Schietinger, Yang-Xing Fu and Donald A. Rowley from the University of Chicago; Yi Zhang from the Medical University of South Carolina, Charleston; and Natalie Bowerman and David M. Kranz from the University of Illinois, Urbana.
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